The progression of many life-threatening diseases such as cancer, AIDS, infectious diseases, immune disorders and cardiovascular disorders are influenced by multiple molecular mechanisms. Due to this complexity, achieving cures with a single agent has been met with limited success. Thus, combinations of agents have often been used to combat disease, particularly in the treatment of cancers. It appears that there is a strong correlation between the number of agents administered and cure rates for cancers such as acute lymphocytic leukemia and metastatic colorectal cancer (Frei, et al., Clin. Cancer Res. (1998) 4:2027-2037; Fisher, M. D.; Clin Colorectal Cancer (2001) August; 1(2):85-6).
Anthracycline antibiotics such as daunorubicin, doxorubicin, epirubicin and their derivatives comprise known antineoplastic agents. Daunorubicin-based drugs, such as daunorubicin hydrochloride, are primarily employed because they intercalate with DNA, affecting various functions of the DNA, including DNA and RNA synthesis. They exhibit activity against acute lymphocytic leukemia, acute granulocytic leukemia, acute myelocytic leukemia, the acute phase of chronic myelocytic leukemia, and acute nonlymphocytic leukemia. Doxorubicin has been shown effective in the treatment of acute leukemias, malignant lymphomas and selected solid tumors such as breast cancer tumors. Idarubicin exhibits similar activity to these antimetabolites and has been used together with cytarabine for adverse karyotype, acute myeloid leukemia (AML). Giles, F. J., et al., J. Clin. Oncol. (2003) 21(9):1722-7.
Cytidine analogs, such as three examples of such analogs including cytarabine, 5-Azacytidine, and gemcitabine, are known antineoplastic agents. For example, these compounds have demonstrated effectiveness at inhibiting DNA synthesis in leukemia and cancer cells. These properties have enabled these compounds to effectively treat acute myelocytic leukemia, acute lymphoblastic leukemia and myelodysplastic syndromes, pancreatic cancer and lung cancer.
US 2004/0052864 discusses the administration of a nonencapsulated DNA methylation inhibitor and a nonencapsulated anti-neoplastic agent, either singularly or in a free drug cocktail, for the treatment of diseases associated with abnormal cell proliferation. However, no pharmaceutical preparations designed to control delivery or half-lives of the drugs were suggested in this publication.
Similarly, U.S. Pat. No. 5,736,155 discusses the preparation of liposome encapsulated neoplastic agents. Single and multiple antineoplastic agents are contemplated as administered simultaneously or sequentially, however, the combination of an anthracycline antibiotic together with a cytidine analog was not suggested.
There are various drawbacks that limit the therapeutic use of drug cocktails. For instance, administration of free drug cocktails often results in rapid clearance of one or all of the drugs before reaching the tumor site. For this reason, many drugs have been incorporated into delivery vehicles designed to ‘shield’ them from mechanisms that would otherwise result in their clearance from the bloodstream. It is well known that liposomes have the ability to provide this ‘shielding’ effect and they are thus able to extend the half-life of therapeutic agents. However, formulation of specific drugs or more than one drug into delivery vehicles has proven to be difficult because the lipid composition of the vehicle often differentially affects the pharmacokinetics of individual drugs. Thus a composition that is suitable for retention and release of one drug may not be suitable for the retention and release of a second drug.
Investigators of the present invention have identified particular delivery vehicle formulations required to accommodate a combination of an anthracycline and a cytidine analog (including daunorubicin and cytarabine-based derivatives), which result in superior drug retention and sustained drug release of each agent. They have further demonstrated that synergistic ratios of these drugs, when encapsulated in liposomes, can be successfully maintained in the blood compartment over time resulting in enhanced efficacy compared to the free drug cocktail and individual liposomal drugs.